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Cardiometabolic microRNA Laboratory

The Cardiometabolic microRNA Laboratory studies how microRNAs alter the expression of key genes involved in the pathogenesis of atherosclerosis and other chronic inflammatory diseases, such as type II diabetes. The team also studies novel mechanisms of inflammation that promote plaque vulnerability. We employ animal models of human disease, in vitro assays of inflammation, cholesterol homeostasis and cellular activation, and analyze pathways of interest in human plasma and atherosclerotic plaque samples.

The laboratory is funded by the Canadian Institutes of Health Research (CIHR), the Ontario Ministry of Research and Innovation, and the JP Bickell Foundation.

Projects

Driven by the interplay between accumulation of excess cholesterol in the arterial wall and the immune system, atherosclerosis is a disease of maladaptive inflammation. The atherosclerotic plaque grows when the rate of macrophage accumulation (via recruitment and proliferation) exceeds that of removal (e.g., via cell death and egress). The removal of excess cholesterol is intricately linked to the inflammatory status of lesions, which in turn underlies the susceptibility to plaque rupture- the ultimate clinical complication of atherosclerosis. Our laboratory recently discovered the role of microRNAs as major regulators of macrophage function in atherosclerosis progression. We have identified the unique coupling of microRNAs to the metabolic and energy control of macrophages and cholesterol removal from lesions, and these discoveries open entirely new avenues to attenuate or reverse the atherosclerotic plaque and its resultant complications. The overall goals of my research program are to discover novel mechanisms that underlie plaque progression and vulnerability, and translate these into tools to ameliorate its clinical impact.

Accordingly, our research program focuses on three integrated research themes: (1) how microRNAs alter macrophage function via extracellular signalling mechanisms; (2) how energy metabolism and metabolic dysregulation within inflammatory cells contributes to atherosclerosis; and (3) how inflammation triggers plaque instability and how this can be used as a diagnostic tool for patients with atherosclerotic disease.

Research objectives: The power of miRNA-based post-transcriptional regulation is amplified by the fact that miRNAs can be secreted into the extracellular space to serve as second messengers of cellular communication to neighbouring and distant cells3. We find that a number of miRNAs are significantly enriched or down-regulated in foam cell exosomes and are predicted to regulate inflammatory pathways and macrophage polarization (M1/M2). We are testing how miRNA-loaded exosomes alter macrophage function in vitro and the propagation of inflammation in atherosclerosis in vivo. We will aim to develop therapeutic anti-sense miRNA and lipid nanoparticles (LNPs) that mimic exosomes for delivery of miRNAs for therapeutic use which are amenable to in vivo imaging if labelled with PET or SPECT tracers that we are currently developing.

Research objectives: We are examining the role of energy-regulating miRNAs in macrophage cholesterol efflux, reverse cholesterol transport and macrophage inflammation. The metabolic status of a cell is a strictly regulated process. For macrophages in the atherosclerotic plaque, metabolic stress comes in the form of excess cholesterol accumulation, and boosting efflux pathways is necessary to effectively remove and detoxify cholesterol to ultimately reduce the progression of inflammation and plaque development. We have previously identified miR-33 as a miRNA that regulate HDL-cholesterol homeostasis and atherosclerosis (Figure). Now we have discovered that miR-33 globally regulates cellular energy status by controlling mitochondrial ATP production and oxidative phosphorylation. We are now studying energy-regulating miRNAs for their role in macrophage cholesterol efflux and inflammatory status. Given that the metabolic pathways that drive atherosclerosis are inextricably linked with those that drive type 2 diabetes, we can extend the discoveries from these metabolic-miRNA pathways in macrophages to models of insulin resistance, as we have done previously with miR-33.